Methods for photodynamic therapy

ABSTRACT

A method of enhancing penetration of a topical composition of 5-aminolevulinic acid (ALA) into tissue for photodynamic therapy includes topically applying ALA to a treatment area to be treated with photodynamic therapy. The method further includes, after the ALA is applied to the treatment area, covering the treatment area with a low density polyethylene barrier. The treatment area is covered with the low density polyethylene barrier prior to light treatment to minimize transepidermal water loss from the treatment area.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. application Ser.No. 15/869,164, filed Jan. 12, 2018, the entire contents of all of whichis incorporated herein by reference.

FIELD

The present disclosure relates generally to methods for photodynamictherapy.

BACKGROUND

Photodynamic therapy (PDT), photodynamic diagnosis (PD), orphotochemotherapy is generally used to treat and/or diagnose severaltypes of ailments in or near the skin or other tissues, such as those ina body cavity. For example, photodynamic therapy or photodynamicdiagnosis may be used for treatment or diagnosis of actinic keratosis ofthe upper extremities (e.g., the dorsal surface of the hand orforearms), scalp or facial areas of a patient. In addition, suchtechniques may be used for treatment and diagnosis of other indications(e.g., acne, warts, psoriasis, photo-damaged skin, cancer) and otherareas of the patient (e.g., the legs or portions of the arms other thanthe forearms).

During one form of photodynamic therapy, a patient is first administereda photoactivatable agent or a precursor of a photoactivatable agent thataccumulates in the tissue to be treated. The area in which thephotoactivatable agent is administered is then exposed to visible light,which causes chemical and/or biological changes in the agent. Thesechanges allow the agent to then selectively locate, destroy, or alterthe target tissue while, at the same time, causing at most only mild andreversible damage to other tissues in the treatment area. One example ofa precursor of a photoactivatable agent is 5-aminolevulinic acid(“ALA”), which is commonly used in photodynamic therapy of actinickeratosis. As they are used here, the terms ALA or 5-aminolevulinic acidrefer to ALA itself, precursors thereof, esters thereof andpharmaceutically acceptable salts of the same. Photosensitizationfollowing application of a topical composition (e.g., a topical solutionor emulsion) containing ALA occurs through the metabolic conversion ofaminolevulinic acid to protoporphyrin IX (PpIX), as discussed in moredetail below. PpIX is a photosensitizer which accumulates in the skin.

For photodynamic therapy to be effective, it is desirable to have apower output that can be controlled for intensity and duration, amongother factors. Illuminators are typically used to provide the properuniformity of light for treatment purposes. These devices generallyinclude a light source (e.g., a fluorescent tube or LED), couplingelements that direct, filter or otherwise conduct emitted light so thatit arrives at its intended target in a usable form, and a control systemthat starts and stops the production of light when necessary.

Photodynamic therapy may be carried out using certain compositions, suchas ALA, in connection with illuminators as described above. Suchcompositions and/or devices are disclosed, for example, in (1) U.S. Pat.No. 5,954,703 to Golub, entitled “Method and apparatus for applying5-aminolevulinic acid,” issued on Sep. 21, 1999, (2) U.S. Pat. No.6,223,071 to Lundahl et al., entitled “Illuminator for photodynamictherapy and diagnosis which produces substantially uniform intensityvisible light,” issued on Apr. 24, 2001, (3) U.S. patent applicationSer. No. 15/371,363 to Boyajian et al., entitled “Method And ApparatusFor Applying A Topical Solution,” published on Jun. 8, 2017 as U.S. Pub.No. 2017/0157379, (4) International Application No. PCT/US2016/056572 toBoyajian et al., entitled “Adjustable Illuminator For PhotodynamicTherapy And Diagnosis,” published on Apr. 20, 2017 as WO 2017/066270,(5) U.S. patent application Ser. No. 15/292,731 to Boyajian et al.,entitled “Adjustable Illuminator For Photodynamic Therapy AndDiagnosis,” published on Apr. 20, 2017 as U.S. Pub. No. 2017/0106205,and (6) U.S. patent application Ser. No. 15/487,991 to Boyajian et al.,entitled “Adjustable Illuminators And Methods For Photodynamic TherapyAnd Diagnosis,” published on Aug. 3, 2017 as U.S. Pub. No. 2017/0216616.The entire contents of the foregoing patents and/or patent applications(1)-(6) are incorporated herein by reference for background informationand the compositions, devices, processes and techniques relating tophotodynamic therapy and diagnosis disclosed therein.

SUMMARY

Through research and experimentation in photodynamic therapeutictechniques, the inventors have found that covering a treatment area withpolyethylene (such as low density polyethylene (LDPE)) for a period oftime prior to light treatment is particularly effective to minimizetransepidermal water loss from the treatment area. Surprisingly, it wasfound that a polymeric barrier having a degree of occlusion more than65% (such as LDPE) was superior to other materials such as polyurethaneand polyvinylidene chloride (PVdC). The low density polyethylene can beapplied to a wide variety of treatment areas, such as the arms, legs,chest, back, portions of the head, and the like, and can be used withdrugs other than ALA.

According to one aspect of the disclosure, a method of enhancingpenetration of a topical composition of 5-aminolevulinic acid (ALA) intotissue for photodynamic therapy is disclosed. The method includestopically applying ALA to a treatment area to be treated withphotodynamic therapy. The method further includes, after the ALA isapplied to the treatment area, covering the treatment area with apolymeric barrier have a degree of occlusion of 65% or more.

According to another aspect of the disclosure, a method of enhancingpenetration of a topical composition of 5-aminolevulinic acid (ALA) intotissue for photodynamic therapy is disclosed. The method includestopically applying ALA to a treatment area to be treated withphotodynamic therapy. The method further includes, after the ALA isapplied to the treatment area, covering the treatment area with a lowdensity polyethylene barrier. The treatment area is covered with the lowdensity polyethylene barrier prior to light treatment to minimizetransepidermal water loss from the treatment area.

According to still another aspect of the disclosure, a method ofphotodynamic treatment of the stratum corneum is disclosed. The methodincludes applying 5-aminolevulinic acid (ALA) to a lesion on the stratumcorneum and reducing evaporation from a portion of the stratum corneumincluding an area where the lesion is present. The method furtherincludes heating the area where the lesion is present before or duringillumination of the area where the lesion is present.

According to a further aspect of the disclosure, a method of using5-aminolevulinic acid (ALA) and a low density polyethylene barrier isdisclosed. The method includes contacting a treatment site with acomposition comprising the ALA so as to wet the treatment site, and,following wetting of the treatment site, covering the wetted treatmentsite with the low density polyethylene barrier.

According to an additional aspect of the disclosure, a method ofenhancing penetration of a topical composition of 5-aminolevulinic acid(ALA) HCl into tissue for photodynamic therapy is disclosed. The methodincludes topically applying the composition to a treatment area to betreated with photodynamic therapy. The method further includes, afterthe composition is applied to the treatment area, covering the treatmentarea with a low density polyethylene barrier prior to light treatment tominimize transepidermal water loss from the treatment area. Thecomposition exhibits a mean plasma concentration (C_(max)) value of ALAless than about 110 ng/mL when the ALA HCl is applied in an amount of354 mg.

BRIEF DESCRIPTION OF THE DRAWINGS

The details of one or more embodiments are set forth in the accompanyingdrawings and the description below. Other features, aspects, andadvantages will become apparent from the description, the drawings, andthe claims. In the drawings, like reference numerals are used throughoutthe various views to designate like components. The drawings are brieflydescribed below.

FIGS. 1A-1B show top views of a main body of an illuminator according toan exemplary embodiment.

FIGS. 2A-2B show perspective views of the main body of the illuminatorof FIGS. 1A-1B.

FIG. 3 shows a perspective view of the illuminator having the main bodyof FIGS. 1A-1B mounted to a stand.

FIG. 4 shows a representative region to be treated in accordance with anexemplary embodiment.

FIG. 5 depicts evaporative water loss rates for a plurality ofmaterials, in accordance with at least one embodiment.

FIG. 6 depicts the degree of occlusion for a plurality of materials, inaccordance with at least one embodiment.

FIG. 7 depicts evaporative water loss rates for a plurality ofmaterials, in accordance with at least one embodiment.

FIG. 8 depicts the degree of occlusion for a plurality of materials, inaccordance with at least one embodiment.

FIG. 9 is a table containing baseline water loss data for the materialsreferred to in FIGS. 5-6.

FIG. 10 is a table containing water loss data following three hours ofwear time for the materials referred to in FIGS. 5-6.

FIG. 11 is a table containing occlusion data for the materials referredto in FIGS. 5-6.

FIG. 12 is a table containing baseline water loss data for the materialsreferred to in FIGS. 7-8.

FIG. 13 is a table containing water loss data following three hours ofwear time for the materials referred to in FIGS. 7-8.

FIG. 14 is a table containing occlusion data for the materials referredto in FIGS. 7-8.

It will be recognized that some or all of the figures are schematicrepresentations for purposes of illustration. The figures are providedfor the purpose of illustrating one or more embodiments with theexplicit understanding that they will not be used to limit the scope orthe meaning of the claims.

DETAILED DESCRIPTION

Various embodiments are described hereinafter. It should be noted thatthe specific embodiments are not intended as an exhaustive descriptionor as a limitation to the broader aspects discussed herein. One aspectdescribed in conjunction with a particular embodiment is not necessarilylimited to that embodiment and can be practiced with any otherembodiment(s).

The following terms are used throughout and are as defined below.

As used herein and in the appended claims, singular articles such as “a”and “an” and “the” and similar references in the context of describingthe elements (especially in the context of the following claims) are tobe construed to cover both the singular and the plural, unless otherwiseindicated herein or clearly contradicted by context. Recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterillustrate the embodiments and does not pose a limitation on the scopeof the claims unless otherwise stated. No language in the specificationshould be construed as indicating any non-claimed element as essential.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The expression “comprising”means “including, but not limited to.” Thus, other non-mentionedsubstances, additives, devices or steps may be present. Unless otherwisespecified, “a” or “an” means one or more.

Unless otherwise indicated, all numbers expressing quantities ofproperties, parameters, conditions, and so forth, used in thespecification and claims are to be understood as being modified in allinstances by the term “about.” Accordingly, unless indicated to thecontrary, the numerical parameters set forth in the followingspecification and attached claims are approximations. Any numericalparameter should at least be construed in light of the number reportedsignificant digits and by applying ordinary rounding techniques. Theterm “about” when used before a numerical designation, e.g.,temperature, time, amount, and concentration including range, indicatesapproximations which may vary by (+) or (−) 10%, 5% or 1%.

As will be understood by one of skill in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

Exemplary Illuminator

FIGS. 1A-1B and 2A-2B illustrate one embodiment of a configurableilluminator as may be used in accordance with the present disclosure.The illuminator includes a main body 100, which preferably has aplurality of individual panels (e.g., panels 10 a-10 e, each of whichare connected in a rotatable manner via nested hinges 50). As shown inFIGS. 2A-2B, on at least one side of a panel, a tab 23 may extend outfrom both the top and bottom of the panel. The tabs 23 are configuredsuch that a side of an adjacent panel may be received between the tabs23, as shown in FIG. 2A, and the hinges 50 are between the tabs 23. Eachpanel contains an array of light emitting diodes (LED) 60. The number ofindividual LEDs arranged in a given array is not particularly limited.Alternatively, other types of light sources may be used, such asfluorescent or halogen lamps. The LED arrays 60 emit light at anappropriate wavelength according to the intended treatment or toactivate the particular photoactivatable agent used in treatment ordiagnosis.

In at least one embodiment, when ALA is used as a precursor of aphotoactivatable agent for the treatment of actinic keratosis, the LEDarrays 60 preferably emit blue light having wavelengths at or above 400nanometers (nm), for example, about 430 nm, about 420 nm or, forexample, 417 nm. However, the LED arrays 60 may also emit visible lightin other ranges of the spectrum, such as in the green and/or red rangesbetween 400 and 700 nm, for example, about 625 nm to 640 nm or, forexample, 635 nm. For example, the LED arrays 60 may also emit lighthaving wavelengths of 510 nm, 540 nm, 575 nm, 630 nm, or 635 nm. Inaddition, the LED arrays 60 may be configured to emit light continuouslyor the LED arrays 60 may be configured to flash the diodes on and offbased on a predetermined interval. Furthermore, the LED arrays 60 may beconfigured such that only one wavelength of light (e.g., blue) isemitted. Alternatively, the LED arrays 60 may be configured such thattwo or more wavelengths of light are emitted from the arrays. Forexample, the LED arrays 60 may be configured to alternately emit bluelight and red light for treatment purposes. In one embodiment, the LEDarrays may also emit red light having wavelengths of 570 to 670 nm.

In one embodiment of the present disclosure, blue light having awavelength of approximately 417 nm is applied at an intensity of 10mW/cm² for 1000 seconds to provide a dose of 10 J/cm². However, theintensity may be increased (for example, doubled) to reduce thetreatment time. For example, the intensity may be increased so as toreduce the treatment time by about one-half. In other embodiments, redlight (such as red light generated by light emitting diodes (LEDs) at,for example, 635 nm) may be used. The red light can provide a dose of,for example, 10 to 75 J/cm² (such as 37 J/cm²), e.g., within 10 minutes.

The ALA can be applied using an applicator as described below, using,for example, a 20% solution of ALA, or can be applied by other meanssuch as glove protected fingers or a spatula. The ALA can be applied in,for example, liquid or gel form and can be applied beyond the lesions tobe treated. In certain applications, materials other than low densitypolyethylene may be used as long as they have a degree of occlusion of65% or more. In certain applications, certain materials may be used aslong as they have a degree of occlusion of 75% or more.

Referring again to the exemplary illuminator shown in FIGS. 1A-1B, themain body 100 of the illuminator may include a mounting head 40. Themounting head 40 may allow for the main body 100 to be mounted to amovable stand 80, which is shown in FIG. 3, to allow a user to easilymove the main body 100 to the appropriate treatment position. The stand80 includes a base 81 and a vertical pillar 82. The base 81 may furtherinclude wheels 87 at its bottom in order to allow the user tohorizontally move the illuminator to an appropriate position. The wheels87 may include locks, such that the stand 80 is prevented from furtherhorizontal movement once positioned. In addition, the vertical pillar 82may be attached to the base 81 at a pivot point 83.

At a top end, the vertical pillar 82 includes a connecting arm 85, whichmay serve as a mounting structure for the main body 100. The connectingarm 85 includes a hinge point 86 such that the main body 100 can bemoved vertically relative to the stand 80. The stand 80 may also includea stabilization arm 84. Once the stand 80 and main body 100 ispositioned, the stabilization arm 84 may be attached to the main body100 to prevent unwanted movement of the main body 100 during treatment.As further shown in FIG. 3, a controller and power supply 90 is mountedto the stand 80 in order to supply electrical power to the main body 100and allow the user to control the main body 100 for treatment purposes.Alternatively, the controller and power supply 90 may be directlymounted to the main body 100. In order to provide a cooling system forthe LED arrays 60, one or more fans 70 may be mounted onto each of thepanels, as shown in FIG. 3.

The controller and power supply 90 may be also connected to the panelsto regulate power to the light source to achieve a desired uniformityand intensity for the target treatment. The control unit may beimplemented as hardware, software, or a combination of both, such as amemory device storing a computer program and a processor to execute theprogram. Alternatively, each panel may have a dedicated control unit toregulate power to the individual LED array on a given panel to allow forfine-tuning of the illuminator, which may further enhance uniformity andincrease efficiency. The LED arrays 60 may be individually configured toincrease the intensity of light emitted from certain diodes to achieveparticular illumination effects.

The illuminator may further include a timer included in the controllerand power supply 90, which can indicate to the user the appropriatelength of exposure time for the particular treatment. The illuminatormay also be programmed with pre-stored light dosing parameters to allowthe user to select a desired treatment type. The pre-stored parametersmay include, for example, pre-stored settings for exposure time, lightintensity, and outputted wavelength. Based on the selected treatment,the illuminator is automatically configured to provide the correctlighting dosage by being supplied with the appropriate power output toachieve the required uniformity for the treatment.

Alternatively, the illuminator can be provided with sensors that detectthe size of the treatment area positioned in front of the illuminator.The sensors then determine the correct light dosing parameters based onthe sensed treatment area. The sensors may detect the adjusted positionof the illuminator manually set by the user. The detected position ofthe illuminator may then be used to indicate the intended treatmentarea. Appropriate light dosing parameters for the specific treatmentarea may then be provided based on the detected position set by theuser.

Adjustable illuminators as described above allow for an infinite amountof configurations that can be adapted for the targeted treatment area.The configurations may range from a flat-plane emitter (as shown inFIGS. 1B and 2B) to a substantially U-shaped configuration (as shown inFIGS. 1A and 2A). Not only can the adjustable illuminator effectivelydeliver a uniform light intensity to surfaces such as the face or scalp,but the adjustable illuminator can also provide a device that can easilybe configured to treat other portions of a patient's body, inparticular, those having smaller curved surfaces, such as the arms andlegs, and in particular, the upper extremities Moreover, the adjustableilluminator may also be easily positioned to deliver a uniform lightintensity to larger treatment areas, such as the back or chest.

The illuminator may irradiate the lesions with a uniform intensity redlight for a prescribed period. In certain embodiments, the illuminatorirradiates the lesions with a uniform intensity blue light for a firstprescribed period and then irradiates the lesions with a uniformintensity red light for a second prescribed period. For example, in someembodiments, the illuminator is configured to irradiate the lesions witha uniform intensity blue light (e.g., 417 nm) at a low intensity (e.g.,about 0.1 J/cm² to about 2 J/cm²) to photobleach, for example,protoporphyrin IX (PpIX) present at the surface of the patient's skin,and irradiate the lesions with a uniform intensity red light (e.g., 635nm) at a high intensity (e.g., about 30 J/cm² to about 150 J/cm²) toactivate PpIX present at deeper layers of the patient's skin, thusavoiding potential damage to the upper layers of the patient's skin.

Furthermore, since the total light dose (J/cm²) is equal to irradiance(mW/cm²) multiplied by time (sec), an additional parameter to becontrolled for delivery of the correct treatment light dose is exposuretime. This may be accomplished by the timer described above, which cancontrol the electrical power supplied to the LED arrays 60appropriately, and which can be set by the physician. Data has shownthat 10 J/cm² delivered from a source with an irradiance density of 10mW/cm², or an irradiance density of about 9.3 to about 10.7 mW/cm²,produces clinically acceptable results for desired treatment areas(e.g., face, scalp, extremities). An adjustable illuminator may deliveran irradiance density of 20 mW/cm² for an exposure time of 500 seconds(8 min. 20 sec) to deliver a clinically acceptable light dose of 10J/cm². In certain embodiments, a lower intensity may be used with alonger exposure time (e.g., 1,000 seconds of exposure time for a lightdose of 10 J/cm²). Alternatively, the adjustable illuminator may includehigher power ranges, such as 30 mW/cm², over an exposure time resultingin a light dose of 10 J/cm². A selected light dose may also beadministered by additionally or alternatively varying the irradiancedensity over treatment time.

In at least one embodiment, a heating element (a heat source) may beprovided. The heat source may be used to heat the region to be treated.According to one embodiment, a method of treatment includes warming upan illuminator so as to cause heat to be emitted from the illuminator,and exposing a treatment site to the illuminator. The heat acceleratesthe conversion of the ALA to porphyrin (e.g., photosensitive porphyrinor proto porphyrin). The relationship between temperature exposure andALA conversion is non-linear, and the enzymatic pathways responsible forthe conversion are highly sensitive to temperature. In at least oneembodiment, increasing the temperature by approximately 2° C. mayapproximately double the rate of production of protoporphyrin IX (PpIX),for example.

The heat may be applied before or during illumination with theilluminator. For example, first, the ALA may be applied. Next, theheating element may be activated, to apply heat to the patient's skinfor a first treatment period for a thermal soak, which may be 20-30minutes, for example. During the heating, the treatment site may or maynot be occluded. In other words, the treatment site may be heated whilebeing occluded.

Following the first treatment period, light may be applied for a secondtreatment period, e.g., about 8-15 minutes. In at least one embodiment,the heat source may be an infrared quartz heater. In at least oneembodiment, the heat source may comprise frame mounted resistance tapeheaters or a plurality of heaters, including at least one selected fromthe group including IR LEDs, resistance cartridge heaters, positivetemperature coefficient heaters, or IR quartz heaters, as mentionedabove. The heat may be deliberately generated and directed towards thearea to be treated, as opposed to ambient heat in the clinical settingor byproduct heat from one or more operating mechanisms of theilluminator.

Administration of ALA

As indicated above, during photodynamic therapy, a total light dose isreceived by a patient over the course of treatment. The total lightdose, in terms of J/cm², may be measured based on emitted irradiance(mW/cm²) over time (in seconds). One example of a treatment method forprecancerous lesions, such as actinic keratosis, by photodynamic therapyutilizing an adjustable illuminator described above in conjunction withALA will now be described.

Essentially anhydrous ALA is admixed with a liquid diluent just prior toits use. The anhydrous ALA may be, for example, the hydrochloride saltof aminolevulinic acid (ALA), an endogenous 5-carbon aminoketone. Thechemical name for ALA HCl, as employed in the embodiments disclosedherein, is 5-amino-4-oxopentanoic acid hydrochloride (molecularweight=167.59). ALA HCl is highly soluble in water. The structuralformula of ALA HCl is represented below:

In at least one embodiment, the ALA is contained in powderized forminside a first ampule. In the first ampule, the amount of ALA as a drysolid may be between 300-400 mg. In at least one embodiment, the amountof ALA HCl is 354 mg. A second ampule contains a solution vehicle. Thesecond ampule contains 1.5 mL of the solution vehicle. The solutionvehicle comprises alcohol (i.e., alcohol as defined by the United StatesPharmacopeia Convention) (ethanol content=48% v/v), water, laureth-4,isopropyl alcohol, and polyethylene glycol.

The first and second ampules are contained inside a plastic applicator.The first and second ampules may be crushed, e.g., by applying fingerpressure, or inside a device configured to exert pressure on the ampule.Once the ampules are crushed, the ALA formerly contained in the firstampule contacts the solution formerly contained in the second ampule,and dissolves in the solution vehicle. The applicator in which theampules were provided may be shaken so as to disperse and dissolve thepowdered ALA in the solution vehicle. Once combined, the resultingsolution is applied to the patient within 2 hours of preparation.

In some embodiments, the ALA may be provided in a composition such as aready-to-use solution or a reconstituted powder for solution, gel, creamor lotion formulation. In another embodiment, the composition comprises5-aminolevulinic acid hydrochloride in an amount of about 10% to about70% w/w based on the total weight of the composition, preferably fromabout 20% to about 50% w/w based on the total weight of the composition,more preferably from about 30% to about 40% w/w based on the totalweight of the composition.

In one embodiment, ALA may be applied in a topical composition with aconcentration of 20%. The ALA admixture is topically applied to thelesions using a point applicator to control dispersion of the ALAadmixture, in at least one embodiment, so as to achieve a substantiallyuniform wetting of the lesion surface with the ALA by contacting the ALAwith the lesion surface. The term “substantial,” or “substantially” asused herein, may refer to any value which lies within the range asdefined by a variation of up to ±15 from the average value. However, inother embodiments, the ALA may be applied digitally (i.e., by firstdisposing the ALA on the gloved fingertips of a practitioner, who thendabs the ALA on the region to be treated), or with a tool such as aspatula.

Occlusion with Barrier

Following application of the ALA to the region to be treated (i.e., thelesion), the region to be treated may be occluded with a polymerbarrier. For example, as shown in FIG. 3, a polymer barrier 200 iswrapped around a region to be treated 300. While the exemplaryembodiment shown in FIG. 3 depicts the barrier 200 as encircling theregion 300, it should be understood that in certain embodiments, thebarrier 200 may only occlude a portion of the region 300. Further, whilebarrier 200 is depicted as substantially cylindrical (e.g., so as toform a sleeve around region 300), the barrier 200 may have a variety ofshapes.

The barrier 200 is shown with a clearance from the region 300 purely forease of illustration in FIGS. 3 and 4. In at least one embodiment,however, the barrier 200 clings or adheres to the region 300 such thatthere is effectively no clearance between the barrier 200 and the region300. The polyethylene barrier may have electrostatic properties thatprovide an adhesive clinging effect such that the barrier tends to stayclose to the surface of the skin, even for prolonged periods. Such aneffect may be particularly enhanced when the skin is wetted with thetopical solution, i.e., when the treatment site is first wetted with thetopical solution, and the barrier 200 is then applied directly on thewetted treatment site.

Experimental results confirmed that employing low density polyethylene(LDPE) for barrier 200 resulted in lower water loss rates and a superiordegree of occlusion. In particular, embodiments with low densitypolyethylene barriers 200 were particularly effective for photodynamictherapy.

FIG. 5 depicts evaporative water loss rates for a plurality of materialsA-E as summarized below in Table 1. The LDPE barriers were found to beespecially conducive to retaining water and allowing for greaterpenetration of the ALA into the region to be treated.

TABLE 1 Barrier Materials A-E Material Distributor Material Code Name orManufacturer Description A Tegaderm ™, 3M Polyurethane Style 1629 BGlad ® Press'n The Glad Products LDPE Seal ® Company C Glad ® Cling WrapThe Glad Products LDPE Company D Stretch-Tite ® Polyvinyl Films,Polyvinylidene Inc. chloride (PVdC) E Saran ™ S C Johnson LDPE PremiumWrap

The measured water loss rates shown in FIG. 5 (and FIG. 7, discussedbelow) are transepidermal water loss rates measured on the dorsalforearms, measured both before and after the barrier 200 had been wornfor 3 hours. The baseline water loss was measured for approximately 30subjects, after a minimum 25-minute acclimation period in a controlledenvironment with less than 50% relative humidity and a temperaturebetween 19-22 deg. Celsius. Such measurements correspond to the barplots labeled “pre” in FIGS. 5 and 7. The subjects had mild to moderatephotodamage on their dorsal forearms. The measurements were made using acalibrated RG1 Evaporimeter System (made by cyberDERM, Inc. of Broomall,Pa.) with DermaLab® transepidermal water loss probes (made by CortexTechnology of Hadsund, Denmark).

A vapor pressure gradient estimation method was used. The probes measurethe temperature and relative humidity at fixed points along the skin,allowing derivation of a value corresponding to evaporative water lossin gm/m² hr. Sampling was performed at 4 inputs/second. The baselinemeasurements indicate the barrier properties of the stratum corneum ofeach subject, prior to applying barrier 200 to the stratum corneum. Themeasurements taken 3 hours after application of the barrier 200 areindicative of the barrier properties of the materials shown in Tables1-2. Such measurements correspond to the bar plots labeled “post” inFIGS. 5 and 7. Each barrier 200 was cut so as to cover a test site areaof 5 cm by 5 cm prior to application. The barrier 200 was secured withhypoallergenic medical tape for the purpose of testing. An area of thesubjects' skin without the barrier 200 was measured as a control.

FIG. 6 depicts degrees of occlusion for a plurality of materials inaccordance with at least one embodiment. More specifically, FIG. 6depicts the degree of occlusion for the materials shown in FIG. 5 andsummarized above in Table 1. The degree of occlusion corresponds to thedecrease in evaporative water loss rate when the subject wore thebarrier 200 as compared to the baseline evaporative water loss rate. Asindicated in FIG. 6, barrier material E, for example, blockedapproximately 85% or more of the water vapor from evaporating from theskin surface. In one embodiment, a polymeric barrier having a degree ofocclusion more than 65% is particularly effective for photodynamictherapy. In one embodiment, a polymeric barrier having a degree ofocclusion more than 75% is particularly effective for photodynamictherapy. Greater occlusivity of LDPE materials such as material Eenhances the penetration of ALA into the tissue by minimizingtransepidermal water loss from the treatment area. The tissue may beskin, in particular, the stratum corneum, or other tissue of a humansubject.

Similar to material E, materials B and C blocked approximately 75% ofthe water vapor from evaporating from the skin surface. Materials A andD, on the other hand, appeared to be semi-occlusive barriers.

FIG. 7 depicts evaporative water loss rates for a plurality of materialsin accordance with at least one embodiment. More specifically, FIG. 7depicts evaporative water loss rates for a plurality of materials W-Zand E as summarized below in Table 2. Barrier material E was the samematerial as shown in Table 1 and discussed above. Materials W-Z includedLDPE and polyvinylidene chloride.

TABLE 2 Barrier Materials W-Z and E Material Distributor Material CodeName or Manufacturer Description W Best-Yet Clear C&S Wholesale LDPEPlastic Wrap Grocers, Inc. X Boardwalk ® PVC Boardwalk PVdC Food WrapFilm, BWK7204 Y Shurfine ® Western Family LDPE Strong and Foods, Inc.Stretchy ® Plastic Wrap Z Premium Plastic Foodhold USA, LLC PVdC Wrap ESaran ™ Premium S C Johnson LDPE Wrap

FIG. 8 depicts degrees of occlusion for a plurality of materials inaccordance with at least one embodiment. More specifically, FIG. 8depicts the degree of occlusion for the materials shown in FIG. 7 andsummarized above in Table 2. As seen in FIG. 8, materials E, W, and Ywere significantly more occlusive than materials X and Z. Materials Xand Z block only approximately 35% of water vapor from evaporating andare thus semi-occlusive in nature. Material E, due to its flexiblenature, easily wraps around the treatment site, which may promote waterretention.

FIG. 9 is a table containing baseline water loss data for the materialsreferred to in FIGS. 5-6. In particular, FIG. 9 provides the baselinemeasurements for each subject for each material A-E shown in Table 1,including mean and standard deviation values. FIG. 10 is a tablecontaining water loss data following three hours of wear time for thematerials referred to in FIGS. 5-6. FIG. 11 is a table containingocclusion data for the materials referred to in FIGS. 5-6. FIG. 12 is atable containing baseline water loss data for the materials referred toin FIGS. 7-8. FIG. 13 is a table containing water loss data followingthree hours of wear time for the materials referred to in FIGS. 7-8.FIG. 14 is a table containing occlusion data for the materials referredto in FIGS. 7-8.

As discussed above, the barrier 200 is used to occlude at least aportion of the region to be treated, e.g., all or part of the dorsalsurface of the hand. In some embodiments, and particularly for largertreatment areas, such as the forearm, an additional structure may beprovided to secure the barrier 200 in place. The low densitypolyethylene wrap may be secured in place with a dressing 210, shown inFIG. 4. In one embodiment, the dressing 210 is a surgical netting suchas Surgilast® Tubular Elastic Dressing Retainer made by Derma SciencesInc. of Plainsboro, N.J. The dressing 210 may be a tubular elasticstretch net designed to serve as a secondary dressing, which applies arelatively light pressure to keep barrier 200 securely in place withoutadhesive tape. That is, the secondary dressing 210 may exert slightcompressive pressure on the barrier 200. The dressing 210 may be asleeve which fits over and around barrier 200. In some embodiments, thesecondary dressing and/or tape may be applied. Following application ofthe ALA and occlusion, treatment may be carried out in accordance withthe exemplary implementations described below.

Treatment Protocols

Once the ALA is applied to the upper extremities, the upper extremitiesmay be occluded for no more than three hours prior to light treatment.For example, the extremities may be occluded for 2-3 hours. As indicatedabove, the ALA is a porphyrin precursor which, when used as part ofphotodynamic therapy, may treat various conditions including minimallyto moderately thick actinic keratoses of the face, scalp or the upperextremities. Accordingly, in at least one embodiment, one or more of aportion of the face, a portion or all of the scalp, or a portion or allof one or more of the upper extremities may be covered in an occlusivebarrier.

Where the ALA is used to treat lesions of the face and scalp without theapplication of an occlusive barrier, following application of the ALA,formation of photosensitive porphyrin and photosensitization of thetreated lesions occurs after 14-18 hours. Between 14 and 18 hours afteradministration of the ALA, the lesions are irradiated by an illuminator.The illuminator may, for example, irradiate the lesions with a uniformintensity blue light for a prescribed period. According to a preferredtreatment, the visible light has a nominal wavelength of 417±5 nm.

The time period for illumination where the ALA is used to treat a lesionon an upper extremity can be significantly shorter when performed withthe application of an occlusive barrier than for the face or scalpsites. The time period is approximately 3 hours between (1) applicationof ALA to the upper extremities and occlusion, and (2) the illuminationof the upper extremities. If the occlusion time exceeds three hours forsome treatment areas, then the skin where the ALA is applied mayexperience irritation. Excessive irritation may be marked by thepresence of itching spots, wheals, flares, or other indicia, includingsymptoms persisting after the treatment session has ended. Inparticular, excessive irritation is marked by adverse cutaneous eventssuch as scaling, crusting, ulceration, rashes, scabbing, tenderness anditching, for example. Three hours represents the nominal maximum timeunder which the upper extremity should be occluded following applicationof ALA, so as to avoid such excessive irritation while maintainingtherapeutic efficacy. Therapeutic efficacy is the clearance of actinickeratosis lesion 12 weeks after PDT. The time period between theapplication of ALA to other body parts (other than the face, scalp andupper extremities) and illumination may be 3 hours, in some embodiments.

Once the occlusive barrier 200 is removed, light treatment as describedabove may be performed, e.g., application of red and/or blue light for alight dose of 10 J/cm². For example, once the barrier 200 is removedwithin 3 hours of being applied, blue light may be applied to theexposed treatment area to deliver a light dose of 10 J/cm², or red lightmay be applied for a 10 J/cm² to 75 J/cm² light dose. In someembodiments, the light may be delivered while the treatment site isstill occluded. In some embodiments, light and heat may be deliveredwhile the treatment site is still occluded.

To treat facial lesions, an illuminator as described above may bepositioned such that the region to be treated is between 2 to 4 inchesfrom a surface of the illuminator, with the patient's nose not less than2 inches from the illuminator surface, and the forehead and cheeks nomore than 4 inches from the surface. The sides of the patient's face andthe patient's ears should be no closer than 2 inches from theilluminator surface.

To treat scalp lesions, an illuminator as described above may bepositioned such that the region to be treated is between 2 to 4 inchesfrom a surface of the illuminator, with the patient's scalp not lessthan 2 inches from the illuminator surface, and no more than 4 inchesfrom the surface. The sides of the patient's face and the patient's earsshould be no closer than 2 inches from the illuminator surface.

To treat lesions on the upper extremities, such as the dorsal surface ofthe hand or the forearms, an illuminator as described above may bepositioned such that the region to be treated is between 2 to 4 inchesfrom a surface of the illuminator. Equipment (e.g., a table) may be usedto support the upper extremity during light treatment so as to enhancethe patient's comfort and stabilize the region to be treated.

Two open-label, pharmacokinetic studies were carried out to evaluate thepotential for systemic exposure of ALA and ALA and protoporphyrin IX(PpIX) when applied topically under occlusion, in a maximal use settingin patients with multiple actinic keratoses (AK) lesions on the upperextremities. In accordance with at least one embodiment, a 20% w/wtopical composition of 5-aminolevulinic acid (ALA) was directly appliedtopically via an applicator to the upper extremities of the patientsfollowed by covering with an occlusive, polyethylene film for a 3 hourincubation period. Light treatment was administered after the incubationperiod. Each subject received 10 J/cm² of visible blue light deliveredat 10 mW/cm².

In the first of the two studies, a total of 29 participants wereenrolled. The participants were males and non-pregnant females, aged 18years or older. Each eligible subject had at least six Grade 1 or Grade2 AK lesions on one upper extremity treatment area and at least 12 Grade1 or Grade 2 AK lesions on the other upper extremity treatment area. Thesubjects received one treatment and were followed until week four aftertreatment. The treatment area, designated at baseline for the durationof the study, was the extensor surface of both distal upper extremities,as defined in the protocol (i.e., the dorsal hands/forearms). In thesecond of the two studies, a total of 14 participants were enrolled.Males and non-pregnant females, aged 18 years or older, with at leastsix Grade 1 or Grade 2 AK lesions on one upper extremity treatment areaand at least 12 Grade 1 or Grade 2 AK lesions on the other upperextremity treatment area, were eligible for the study.

The topical application of the ALA to the upper extremities resulted inlower systemic exposure to ALA and PpIX than intravenous and oraldosing. The method according to at least one embodiment includesapplication of up to two topical solution compositions each containingabout 354 mg ALA. The dosing using the topical solution was compared tointravenous and oral dosing in an amount of about 100 mg ALA. Asindicated above, strength of the ALA was about 20% by weight. Thetopical dosing was observed to result in a mean plasma concentration(C_(max)) value of ALA of less than about 110 ng/mL. The term “C_(max),”as used herein refers to maximum observed plasma concentrations based onactual values measured following study medication application.

In particular, following topical applications, the geometric meanmaximum plasma concentration was about 98 ng/mL at a median of 2 hoursfollowing application, with the geometric mean area-under-the-curve(AUC_(t)) of 577 ng*h/mL, with variability from about 94% to about 170%.Following a baseline correction, the ALA geometric mean maximum plasmaconcentration was 80 ng/mL at a median of 2 hours, with a geometric meanAUC_(t) of 282 ng*h/mL. In an embodiment, the topical solution, whenapplied in a strength of about 20% by weight, exhibits a geometric meanarea under curve (AUC_(T)) value of ALA less than about 350 ng·hr/mL.The term “AUC_(t),” as used herein, refers to the area under the plasmaconcentration-time curve up to the last quantifiable/non-negative plasmaconcentration.

In another experiment, following topical applications, the geometricmean maximum plasma concentration was about 61 ng/mL at a median of 2hours following application, with the geometric mean AUC_(t) of 727ng*h/mL, with variability from about 30% to about 152%. Following abaseline correction, the ALA geometric mean maximum plasma concentrationwas 39 ng/mL at a median of 2 hours, and a geometric mean AUC_(t) of 182ng*h/mL. The estimated bioavailability following topical application of354 mg ALA with occlusion was about 1.0%. In one embodiment, thesystemic bioavailability following topical application of 354 mg ALA HClis less than about 5%. The term “bioavailability” as used herein refersto the rate and extent of absorption and is determined by AUC_(T) andC_(max) values.

In accordance with at least one embodiment, a method of photodynamictherapy was carried out to treat lesions on the upper extremities in amulti-center randomized, parallel-group, evaluator-blinded andvehicle-controlled study of 269 patients with 4-15 mild to moderateactinic keratoses. The actinic keratoses were present on the upperextremities, more specifically, on the dorsal surface of the handsand/or the forearm area between the elbow and the base of the fingers.Subjects ranged from 45 to 90 years of age (mean 68 years) and 90% hadFitzpatrick Skin Type I, II or III. Subjects were randomized totreatment in a 1:1 ratio. ALA was applied to lesions on the dorsalsurface of one hand or the forearm for each subject, and the dorsalsurface of the hand or the forearm was then occluded with low densitypolyethylene barrier for three hours. Following removal of the lowdensity polyethylene barrier, a 10 J/cm² dose of blue light wasdelivered at 10 mW/cm², with treatment repeated after 8 weeks if anylesion(s) remained in the treatment area.

Complete clearance (i.e., resolution of the actinic keratoses) wasachieved by 31% of the subjects (that is, 42 out of 135 subjects)receiving ALA. Complete clearance was achieved at twelve weeks afterinitial treatment, as compared to 13% of subjects (that is, 17 out of134 subjects) receiving only the solution vehicle (without the ALA). Ofthe subjects who achieved complete clearance at twelve weeks, atwelve-month follow-up evaluation was performed, which indicated thatthose subjects had a recurrence rate of 58%. The recurrence ratecorresponds to the percentage of subjects with at least one recurrentlesion during the 12 month follow up period following the evaluation attwelve weeks who had previously achieved complete clearance at twelveweeks following treatment.

The present disclosure thus provides a method for photodynamicallytreating a surface of a patient, and occluding the patient's skin aspart of treatment. The patient may be illuminated to treat actinickeratosis, acne, photo-damaged skin, cancer, warts, psoriasis, or otherdermatological conditions.

While this specification contains certain specific implementationdetails, these should not be construed as limitations on the scope ofwhat may be claimed, but rather as descriptions of features specific toparticular implementations. Certain features described in thisspecification in the context of separate implementations can also beimplemented in combination in a single implementation. Conversely,various features described in the context of a single implementation canalso be implemented in multiple implementations separately or in anysuitable subcombination. Moreover, although features may be describedabove as acting in certain combinations and even initially claimed assuch, one or more features from a claimed combination can in some casesbe excised from the combination, and the claimed combination may bedirected to a subcombination or variation of a subcombination.

It is important to note that the construction and arrangement of theilluminator system shown in the various example implementations areillustrative only and not restrictive in character. All changes andmodifications that come within the spirit and/or scope of the describedimplementations are desired to be protected. It should be understoodthat some features may not be necessary and implementations lacking thevarious features may be contemplated as within the scope of thedisclosure, the scope being defined by the claims that follow. When thelanguage “a portion” is used the item can include a portion and/or theentire item unless specifically stated to the contrary.

Additional advantages and modifications will readily occur to thoseskilled in the art. Therefore, the invention in its broader aspects isnot limited to the specific details and representative devices andmethods, shown and described herein. Accordingly, various modificationsmay be made without departing from the spirit and scope of the generalinventive concept as defined by the appended claims and theirequivalents.

What is claimed is:
 1. A method of photodynamic treatment of actinickeratosis, comprising: applying 5-aminolevulinic acid (ALA) in gel formto an actinic keratotic lesion on the stratum corneum of an upperextremity; and reducing evaporation from a portion of the stratumcorneum including an area where the lesion is present using an occlusivedressing, wherein reducing evaporation comprises applying the occlusivedressing to the area and keeping the occlusive dressing on the area at atemperature between about 19° C. to about 22° C.
 2. The method of claim1, wherein reducing evaporation comprises applying a low densitypolyethylene wrap as the occlusive dressing and holding the low densitypolyethylene wrap in place with an elastic net.
 3. The method of claim1, wherein reducing evaporation comprises applying the occlusivedressing to the area, and securing the occlusive dressing by a tubularelastic stretch netting.
 4. The method of claim 1, further comprisingilluminating the lesion with a dose of light of 37 J/cm².
 5. The methodof claim 1, further comprising covering the occlusive dressing withmaterial.
 6. The method of claim 5, wherein covering the occlusivedressing with material comprises placing the material over and aroundthe occlusive dressing.
 7. A method of photodynamic treatment of actinickeratosis, comprising: applying 5-aminolevulinic acid (ALA) in gel formto an actinic keratotic lesion on the stratum corneum of an upperextremity; and reducing evaporation from a portion of the stratumcorneum including an area where the lesion is present using an occlusivedressing, wherein reducing evaporation further comprises keeping theocclusive dressing on the area at a temperature between about 19° C. toabout 22° C.
 8. The method of claim 7, wherein reducing evaporationcomprises applying a low density polyethylene wrap as the occlusivedressing and holding the low density polyethylene wrap in place with anelastic net.
 9. The method of claim 7, wherein reducing evaporationcomprises applying the occlusive dressing to the area, and securing theocclusive dressing by a tubular elastic stretch netting.
 10. The methodof claim 7, further comprising illuminating the lesion with a dose oflight of 37 J/cm².
 11. The method of claim 7, further comprisingcovering the occlusive dressing with material.
 12. The method of claim11, wherein covering the occlusive dressing with material comprisesplacing the material over and around the occlusive dressing.
 13. Amethod of photodynamic treatment of actinic keratosis, comprising:applying a topical composition of 5-aminolevulinic acid (ALA)hydrochloride at a concentration of 20% by weight to an actinickeratotic lesion on the stratum corneum of an upper extremity; andreducing evaporation from a portion of the stratum corneum including anarea where the lesion is present using an occlusive dressing, whereinreducing evaporation comprises applying the occlusive dressing to thearea and keeping the occlusive dressing on the area at a temperaturebetween about 19° C. to about 22° C.
 14. The method of claim 13, furthercomprising covering the occlusive dressing with material.